Process for the separation of the optically active isomers of lobelia alkaloids, their derivatives, and allied compounds



Patented June 20, 1933 UNITEDI'STATES PATENT? OFFICE HEINRICH WIELANID, OF MUNICH, GERMANY, ASSIGNOR TO C. H. BOEHRINGER SOI-IN AKTIENGESELLSCHAFT, OF NIEDERJNGELHEIM-ON-THE-RHINE, GERMANY, A COR- PORATION OF GERMANY PROCESS FOR THE SEPARATION OF THE OPTIGALLY ACTIVE ISOMER-S OF LOBELIA ALKALOIDS, THEIR DERIVATIVES, AND ALLIED COMPOUNDS 1 I .No Drawing. Original application filed June 24, 1929, Serial N0.-373,467, and in Germany June 29, 1928..

Divided and this application fi1ed March 13, 1931. Serial No. 522,527; I

This application is a division of the process described in my prior application, Ser. No. 373,467, for the Preparation of lobelia alkaloids, their derivatives, and allied compounds,

5 which application was filed on June 24, 192%).

According to my aforesaid application it is possible in the case of compounds, whlch contain in a ring system, consisting of carbon atoms and one nitrogen atom, at least one 0 side chain with an alcoholic hydroxyl group in the 2- or 6-position to the nitrogen atom, to convert one or both of the hydroxyl groups contained in the side chains into carbonyl groups by treatment with the usual oxidizlng agents, such as permanganate or pyrolusite in dilute sulphuric acid.

In this way it is possible, for example to convert the lobelanidine contained as a comparatively inactiveby-product in the mother liquors from the preparation of d,l-lobel1ne (lobelidine) and having the formula:

It is possible in general to convert in this Way one or both of the side chain hydroxyl groups in compounds of the type /CHOH Rx where R, R and R represent an alkyl or aralkyl residue or hydrogen, as well as in substitution products of such compounds, into carbonyl groups.

It has been found that such compounds obtained according to the process of my aforesaid prior application, which contain a carbonyl group in one side chain and a hydroxyl group attached to an asymmetric carbon atom in the other side chain, such as d,l-lobeline, d,l.nor-lobeline or their substitution products, can be resolved with the aid of suitable optically active acids, such as tartaric acid or with the aid of the salts of the said acids into their optically active components. Thus for example by causing neutral tartrates to react with salts of d,l-lobeline a mixture of varying composition, depending upon the working conditions, of tartrates of l-lobeline is obtained, from which pure l-lobeline is obtained by repeated recrystallization and separation of the base, whilst d,lobeline may be recovered from the mother liquors.

Ewample der undissolved by the ether. The ethereal solution is concentrated and yields 1.8 gms. of crude d,l-lobeline of melting point 10 l 110 C. (about 80% of pure d,l-lobe1ine can be recovered therefrom).

10 gms. of the hydrochloride of the lobeline obtained in themanner described are dissolved in 20 cos. of water and treated with the calculated quantity of 6.2 gms. of sodium tartrate dissolved in 10 cos. of water. A light oil separates out and soon sets, particularly on seeding with the tartrate of l-lobeline. On recrystallizing long needles, melting at C. consisting of the tartrate of l-lobeline and polyhedral crystal clusters having a melting point of 180 (3., which presumably contain l-lobeline-sodium 'tartrate, are obtained side by side. A base of melting point 130131 C. which consists of l-lobeline is obtained from both salts, and has methyl-piperidine (d,l-lobeline) with the aid of a substance chosen from the group consisting of optically active organic acids and salts of said organic acids.

6. A process which consists in resolving into its optically active components the racemic 2 (,B-hydroxy-B-phenethyl)-6-phenacyl N -1nethyl-piperidine d,l lobeline) with the aid of a substance chosen from the group consisting of optically active tartaric The substantially more-readily soluble tartrate of d-lobeline maybe recovered from the mother liquor.

lVhat I claim is r 1. A process which consists in resolving into their optically active compounds racemic compounds which in a nucleus of the group consisting of piperidine and an N-alkylated piperidine, contain a B-hydroXy-B-phenethyl group in the 2-posit-ion to the nitrogen atom and a phenacyl group in the 6-position, with the aid of a member of the group consisting of optically active organic acids and salts of said organic acids.

2. A process which consists in resolving into their optically active components racemic compounds which in a piperidine nucleus contain a ,8hydroXy-,B-phenethyl group in the 2-position'to the nitrogen atom and a p'henacyl group in the 6-pos'ition with the aid of a substance'chosen from the group consistng of tartartic acid and salts of tartaric ac1 '3.A process which consists in resolving into their optically active components racemic-compounds which in an N-alkylated piperidine nucleus contain a fl-hydroxy-B- phenethyl group in the 2-position to the nitrogen atom and a phenacyl group inthe 6-position, with the aid of a member of the group consisting of optically active organic acids, and salts of said optically active organic acids. v a 4. A process which consists in resolving into its optically active components the racemic 2 (B-hydroxyB-phenethyl) fi-phenacylpiperidine (d,l-nor-lobeline) with the aid of a substance chosen from the group consisting of optically active organic acids and salts of said optically active organic acids.

5. A process which consists in resolving into its optically active components racemic 2- (5 -hydroxy p phenethyl) 6-phenacyl-N- 

